1. Technical Field of the Invention
The present invention relates to cosmetic or pharmaceutical compositions containing an effective amount of a pyrimidine N-oxide compound, for inducing and/or stimulating the growth of human keratin fibers and in particular the hair and the eyelashes, and/or for reducing their loss.
This invention also relates to a cosmetic treatment process (regime or regimen) for stimulating the growth of human keratin fibers such as the hair and the eyelashes and/or for reducing their loss, and to the use of the subject pyrimidine N-oxide compounds as NO-donating active agents and/or as agents for inhibiting lysyl-hydroxylase, in particular for inducing and/or stimulating the growth of the hair or the eyelashes and/or for reducing their loss.
The present invention also relates to novel pyrimidine N-oxide compounds with NO-donating and/or lysyl-hydroxylase inhibiting activity.
2. Description of Background and/or Related and/or Prior Art
Hair growth and hair renewal are mainly determined by the activity of the hair follicles and of their matrix environment. Their activity is cyclical and comprises essentially three phases, namely, the anagenic phase, the catagenic phase and the telogenic phase.
The anagenic phase (active phase or growth phase), which lasts several years and during which the hair gets longer, is followed by a very short and transient catagenic phase which lasts a few weeks. During this phase, the hair undergoes a change, the follicle becomes atrophied and its dermal implantation appears higher and higher.
The terminal phase or telogenic phase, which lasts a few months, corresponds to a resting phase of the follicle and the hair ends up falling out. At the end of this rest period, a new follicle is regenerated in situ and another cycle begins.
The head of hair is thus under permanent renewal, and, out of the approximately 150,000 hairs that make up a head of hair, about 10% are at rest and will be replaced within a few months.
In adulthood, the vascular system of the skin is complete and no longer changes, except in the hair follicles, where it undergoes large changes with each hair cycle. Specifically, the hair follicles are a richly innervated and highly vascularized cutaneous structure. The phenomenon of development of capillary circulation in the hair follicles is known as angiogenesis. At the start of each anagenic phase, it is necessary to develop a high activation of angiogenesis in order to redevelop the perifollicular vascular capillary network. The involution of this capillary network and the disappearance of the blood vessels of the dermal papilla go hand in hand with the change of phase and the passage into the catagenic phase. At this stage, the blood capillaries collapse and disappear.
In parallel, in the alopecic areas, a perifollicular fibrosis becomes established, the follicles reduce in size cycle after cycle and the specific vascularization of the bulbs gradually diminishes.
The phenomenon of angiogenesis observed during the anagenic phase is dependant on many trophic factors, cytokines or other biologically active molecules provided by the blood circulation or produced locally, in particular by the fibroblasts of the dermal papilla or the keratinocytes of the hair bulb. Among these trophic factors, mention may be made of endothelial cell growth factor (also known as vascular endothelial growth factor (VEGF)). This factor is essential for angiogenesis and increases the vascular permeability. Studies have shown that the expression of this factor was increased during the anagenic phase of the hair cycle. Thus, this factor contributes towards maintaining a functional capillary vascularization around the hair follicle and especially at the base of the bulb and of the dermal papilla, and also towards supplying nutrients required for good growth of the hair.
The perifollicular capillary circulation thus plays a fundamental role in the process of hair growth by supplying the factors and nutrients required for the growth of this follicle.
The natural loss or falling-out of the hair may be estimated, on average, as being a few hundred hairs per day for a normal physiological state. This process of permanent physical renewal undergoes a natural change during aging; the hairs become finer and their cycles shorter.
Moreover, in certain dermatoses of the scalp with an inflammatory component, for instance psoriasis or seborrhoeic dermatitis, hair loss may be greatly accentuated and the follicle renewal cycle may be highly disrupted.
In addition, various causes may result in a substantial, temporary or permanent loss of hair. This may be loss and impairment of hair at the terminal stage of pregnancy (post-partum), during states of dietary malnutrition or imbalance, or during states of asthenia or of hormonal dysfunction, as may be the case during or at the terminal stage of the menopause. It may also be a case of loss or impairment of the hair related to seasonal phenomena.
It may also be a matter of alopecia, which is essentially due to a disturbance in hair renewal, resulting, in a first stage, in acceleration of the frequency of the cycles to the detriment of the quality of the hair, and then of their quantity. This then results in a gradual impoverishment of the head of hair and in gradual thinning of the hair together with isolation of the bulbs due to progressive thickening of the perifollicular collagen matrix and of the outer connective sheath. Revascularization is thus made more difficult cycle after cycle. The successive growth cycles result in hairs that are finer and finer and shorter and shorter, gradually transforming into an unpigmented down. Certain areas are preferentially affected, especially the temporal or frontal lobes in men, and a diffuse alopecia of the crown of the head in women.
As a result of the fundamental role of the perifollicular capillary circulation mentioned above, any defect in this circulation will result in a reduction in the supply of nutrients and gases (especially oxygen) required for hair growth, leading to disturbances in the growth of the hair and the gradual establishment of alopecia.
The term alopecia also covers a whole family of afflictions of hair follicles whose final consequence is the permanent, partial or general loss of the hair. This is more particularly a matter of androgenic alopecia. In a large number of cases, early loss of hair occurs in genetically predisposed individuals; this is then a matter of androchronogenetic alopecia. This form of alopecia especially affects men.
It is moreover known that certain factors, such as hormonal imbalance, physiological stress or malnutrition, can accentuate the phenomenon of hair loss.
In general, any factor that results in an increase in the blood supply to the hair follicles, either by activating angiogenesis, combating its regression or acting on the capillaries to limit their constriction, will have a beneficial effect on the energy supply required for good growth of these follicles.
Compositions for suppressing or reducing alopecia, and especially for inducing or stimulating hair growth or reducing hair loss have been sought for many years in the cosmetics and pharmaceuticals industries. One of the routes explored is the maintenance of the vascularization around the hair follicle.
Thus, one of the compounds known to maintain perifollicular vascularization is verapamil, which is a powerful type L calcium-channel antagonist (IC50Ca2+=38 nM). Verapamil and other calcium-channel antagonists such as diltiazem and nifedipine are described as being active in the treatment of hair loss, in particular as a result of their effects on capillary circulation (cf. the documents by Shiseido JP 88/062680 and Coppe J. BE/89/000305). IC50Ca2+is the concentration that inhibits 50% of the release of Ca2+.
In addition, documents exist describing the use of NO (nitrogen monoxide) donors for application to the scalp, to stimulate hair growth by acting on the capillary circulation of the scalp. Thus, the patent by Proctor (EP-0-327,263) describes the use of compounds producing the NO radical, in combination with reducing agents, antioxidants and hydroxyl-radical scavengers. Another patent by E. Fossel (WO 99/13717) describes the use of arginine and derivatives thereof as an NO-synthase substrate for the in vivo formation of NO and their use (inter alia) in the treatment of alopecia. Another patent by Shiseido (JP-A-07,016,023) also describes the use of arginine and its derivatives in the treatment of alopecia.
These known substances have adverse effects. In particular, they have multiple activities, which may disrupt the ionic and physiological equilibrium of the skin cells. In other words, their multiple activity makes it difficult to control their action on cells.